Lorigerlimab, a bispecific PD-1×CTLA-4 DART molecule in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): A phase 1 expansion (exp) cohort.
Authors: Jason J. Luke, Manish Sharma, Sreenivasa R Chandana, Iwona A. Lugowska, Cezary Szczylik, Jakub Zolnierek, Gregory Michael Cote, Charlene Mantia, Rafal Dziadziuszko, Rachel E. Sanborn, Denise Casey, Lori Long, Ashley Ward, Patrick Kaminker, Angela Joubert James, Tiziana Di Pucchio, Bożena Cybulska-Stopa
Journal: Journal of Clinical Oncology (2023)

155 Background: Lorigerlimab (MGD019) is an investigational, bispecific Fc-bearing (IgG4) DART molecule designed to enhance CTLA-4 blockade on dual expressing, tumor infiltrating lymphocytes, while maintaining maximal PD-1 blockade on PD-1 expressing cells. Lorigerlimab has approximate dose proportional PK across 1–10 mg/kg IV dosing Q3W, with sustained PD-1 receptor occupancy evident at doses ≥1 mg/kg Q3W. MGD019-01 is a global first-in-human dose finding and activity estimating study of lorigerlimab in advanced solid tumors (AST). Methods: The exp phase of MGD019-01 evaluates single agent safety, PK, and antitumor effects of lorigerlimab at the recommended dose for exp of 6 mg/kg IV Q3W in 4 tumor specific cohorts. Confirmed responses were noted in each cohort. Preliminary results of the mCRPC cohort are reported here. Response evaluable pts received ≥1 dose and had ≥1 postbaseline imaging evaluation. Measurable lesions were evaluated per RECIST v1.1 and skeletal metastases assessed by bone scan. Prostate specific antigen (PSA) response was defined as a ≥50% (PSA50) or ≥90% (PSA90) PSA decline from baseline with confirmation ≥3 weeks later. Expression of proliferation marker, Ki67, and inducible costimulator (ICOS) by peripheral T cells was assessed by flow cytometry. Results: At data cutoff (9/10/22), 127 pts with AST received ≥1 dose of lorigerlimab 6 mg/kg. Median exposure was 10 weeks (range, 0.1, 94.4) with median of 4 infusions. 6 pts remain on therapy; 36 discontinued for PD (n=13), AEs (n=17), or patient/physician decision (n=6). Treatment related adverse events (TRAE) occurred in 109/127 (85.8%) pts. TRAEs occurring in ≥15% of pts were fatigue, pruritus, hypothyroidism, pyrexia. Rates of grade ≥3 TRAEs and immune-related AEs were 32.3% and 7.9%, respectively. AEs leading to drug discontinuation occurred in 22.8% of pts. There were no fatal AEs related to lorigerlimab. In the mCRPC exp cohort (n=42), pts had a median of 2 prior lines of therapy for CRPC, &gt;80% received prior ART or taxanes; 88% had visceral (liver, 26%; lung, 26%) or nodal disease and 95% had bone metastases. 42 pts were PSA response evaluable; 35 were RECIST evaluable. ORR was 25.7% (9/35; 9 confirmed PRs). Median duration of response was 16.1 weeks (range 6–25+ weeks). 5 responders remain on study, 4 discontinued for unrelated fatal AEs: COVID-19 (2) cardiac arrest (1) C. difficile infection (1). Confirmed PSA50 and PSA90 response rates were 28.6% (12/42) and 21.4% (9/42), respectively. Increased frequencies of Ki67+ and ICOS+ T cells were observed on day 8 posttreatment compared to pretherapy per the flow cytometry analyses from 35 pts. Conclusions: Lorigerlimab demonstrates a manageable safety profile with evidence of encouraging and durable antitumor activity in a chemotherapy refractory mCRPC population. Randomized evaluation of lorigerlimab in mCRPC is warranted. Clinical trial information: NCT03761017 .